Summary: Ketamine has transformed care for many people with treatment-resistant depression (TRD), often relieving suicidal thoughts and crushing low mood within hours instead of weeks. Its major limitation, however, is how quickly those benefits fade—typically within days. A new study now identifies why ketamine’s effects are so short-lived and points to ways to make them last much longer.
Researchers have identified the enzyme NOX-1 as a molecular “off-switch” that undermines ketamine’s antidepressant effects. By inhibiting NOX-1 or by using a new AMPA receptor modulator called K-4, the team extended antidepressant-like responses from a few days to more than two weeks in animal models.
Key Facts
- NOX-1 as a critical regulator: NOX-1 (NADPH oxidase-1) produces reactive oxygen species that can disrupt brain circuits and erase the synaptic changes ketamine initiates. Suppressing NOX-1 preserves those beneficial changes.
- K-4, a novel AMPAR modulator: The compound K-4 enhances AMPA receptor function and, unlike currently available agents, reduces NOX-1 expression naturally—producing sustained behavioral benefits for 14+ days after a single dose in the study.
- Resetting dysfunctional circuits: Both NOX-1 suppression and K-4 reduce pathological burst firing in the lateral habenula (a region linked to negative mood) and rebalance excitatory signaling in the medial prefrontal cortex, supporting longer-lasting antidepressant effects.
- Clinical directions: The findings suggest two promising paths: pairing ketamine with NOX-1 inhibitors to extend its clinical effect, or developing K-4–like AMPAR modulators as a new class of longer-lasting glutamate-based antidepressants.
Source: Yokohama City University
About 30% of people with major depressive disorder do not respond adequately to standard antidepressants, a condition known as treatment-resistant depression (TRD). Ketamine has offered a powerful, rapid alternative for these patients, often producing mood improvement within hours. But the transient nature of its benefits—usually lasting days to a couple of weeks—limits its long-term utility, and repeated dosing introduces cost, access, and safety concerns.
A research team led by Professor Takuya Takahashi and Dr. Waki Nakajima at Yokohama City University set out to uncover the molecular and circuit-level mechanisms that determine how long ketamine’s antidepressant effects last. Their study, published in Molecular Psychiatry (March 23, 2026), identifies NOX-1 as a key target for extending ketamine’s therapeutic window.
The investigators focused on AMPA receptors (AMPARs), which mediate fast excitatory transmission in the brain and play a central role in ketamine’s action. They developed K-4, a positive allosteric modulator of AMPARs, and tested it in Wistar Kyoto rats, a validated animal model of TRD.
K-4 produced rapid antidepressant-like responses that remarkably persisted for at least two weeks after discontinuation, outlasting ketamine and other AMPAR enhancers in the same model. To understand why, the team analyzed gene expression in the medial prefrontal cortex (mPFC), a brain region critically involved in mood regulation, and found significantly reduced levels of NOX-1 in K-4–treated animals.
The reduced NOX-1 expression suggested a mechanism: excessive NOX-1 activity may generate oxidative stress that reverses ketamine-induced synaptic improvements. To test this directly, researchers combined ketamine with a pharmacological NOX-1 inhibitor and observed an extended antidepressant-like effect compared with ketamine alone. They achieved the same outcome by selectively knocking down NOX-1 in the mPFC using genetic tools.
Electrophysiological recordings revealed that both K-4 treatment and ketamine paired with NOX-1 inhibition suppressed pathological burst firing in the lateral habenula and restored the excitatory–inhibitory balance in the mPFC—circuit changes that align with prolonged behavioral improvement.
“These results illuminate molecular and circuit-level processes that control the duration of antidepressant responses,” says Prof. Takahashi. “Targeting NOX-1 or developing AMPAR modulators like K-4 opens practical routes to sustain ketamine’s benefits or to create new long-acting treatments.”
The findings point toward two near-term research and development strategies: (1) testing NOX-1 inhibitors as adjunctive treatments that could extend ketamine’s effect in clinical settings, and (2) advancing K-4 or related AMPAR positive allosteric modulators as standalone, longer-lasting glutamate-based antidepressants. Both approaches could help reduce the burden of repeated ketamine dosing and improve long-term outcomes for patients with TRD.
For people whose depression does not respond to conventional therapies, these advances represent a meaningful step toward more durable relief.
Funding information
This research was supported by JSPS KAKENHI Grant Numbers JP20H05922 and JP20H00549, AMED Grants JP19dm0207072 and JP24wm0625304, the Takeda Science Foundation, and additional JSPS KAKENHI awards (JP23K10432, JP25K22755, JP24K02781).
Key Questions Answered:
A: Ketamine rapidly restores synaptic connections and circuit function, but the brain’s own biochemical response—specifically increased NOX-1 activity—appears to create oxidative stress that undoes those repairs. Blocking NOX-1 helps preserve the synaptic changes ketamine triggers.
A: No. K-4 is an AMPAR positive allosteric modulator, a different class of compound that enhances excitatory transmission and reduces NOX-1 expression. Its major advantage in the study was markedly longer-lasting effects—at least two weeks after a single dose.
A: Findings in Wistar Kyoto rats are promising but preliminary. Human clinical trials will be required to evaluate safety and efficacy. The researchers expect this work could speed development of adjunctive NOX-1 inhibitors or new AMPAR modulators for TRD in the coming years.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The referenced journal paper was reviewed in full.
- Additional context was added by editorial staff.
About this psychopharmacology research news
Author: Public Relations Division
Source: Yokohama City University
Contact: Public Relations Division – Yokohama City University
Image: The image is credited to Neuroscience News
Original Research: Open access. “NADPH oxidase-1 suppression prolongs the antidepressant-like effect of Ketamine” by Waki Nakajima et al., Molecular Psychiatry. DOI: 10.1038/s41380-026-03527-1
Abstract
NADPH oxidase-1 suppression prolongs the antidepressant-like effect of Ketamine
Subanesthetic ketamine doses produce rapid antidepressant effects in treatment-resistant depression, but these benefits are typically short-lived after a single administration. This study explored mechanisms that could sustain ketamine’s efficacy, focusing on AMPA receptors (AMPARs), which are key effectors in ketamine’s action. The researchers developed K-4, a novel AMPAR positive allosteric modulator, and tested it in Wistar Kyoto rats, a TRD model.
K-4 produced longer-lasting antidepressant-like effects than ketamine. RNA sequencing of the medial prefrontal cortex revealed reduced expression of NOX-1 in K-4–treated animals. Combining ketamine with a NOX-1 inhibitor, or knocking down NOX-1 in the mPFC, prolonged ketamine’s behavioral effects and suppressed pathological bursting in the lateral habenula. These results indicate that NOX-1 suppression can extend ketamine’s antidepressant-like effects and represents a promising target for maintenance strategies in TRD.